Environmental factors have the ability to facilitate overeating and weight gain in otherwise healthy individuals, and therefore contribute to the development of obesity. Importantly, overeating under the influence of environmental factors might occur even in the absence of any deficiencies in metabolic processes. Among such factors, external cues associated with food availability stimulate and sustain food intake independently of any deficits in nutritional state. While research with animal models has established the amygdalar complex as a brain region fundamental for the influence of food-associated cues on food intake, much less is known about which brain circuits support such mechanisms in humans. The overall aim of this proposal is to employ behavioral and functional neuroimaging methods to test a novel model of how the environment and metabolism influence processing in the amygdala-hypothalamic circuit and promote overeating. In a series of studies we will test whether the human amygdala mediates the influence of food-associated cues on food intake and body weight. Our functional neuroimaging data will allow us to determine whether the magnitude of these amygdale responses to food cues is a reliable predictor of longer-term (e.g., twelve months) weight gain. The specific aims of the proposed project are as follows: (1) To determine whether changes in amygdala responses to food stimuli following satiation are altered in overweight/obese human subjects, and whether such abnormal responses function as predictors of weight gain susceptibility; (2) to determine whether amygdala responses to foods are altered during acute stress, and if so, whether this response is enhanced in overweight/obese subjects and thus predicts weight gain susceptibility; and (3) to determine whether changes in amygdale responses to aromas and flavors associated with caloric value are altered in overweight/obese subjects, whether these changes are associated with metabolic factors, and whether abnormal responses to caloriepaired flavor cues function as predictors of weight gain susceptibility. Our general hypothesis states that the magnitude of amygdala responses to food cues in an individual yields quantitative predictions on weight gain susceptibility over a period of 12 months. Consistent with this hypothesis, our preliminary data shows that amygdala response to food cues is enhanced in overweight individuals and that the magnitude of such response is a reliable predictor of weight gain. The proposed studies will further our understanding of the brain mechanisms mediating the influence of environmental factors on food intake and body weight in humans, and in particular proposes human amygdala neural responses to environmental factors as a quantitative predictor of weight gain susceptibility over extended periods of time. PUBLIC HEALTH RELEVANCE: Environmental factors influence food intake and are important contributors to the development of obesity. However, the brain mechanisms underlying the influence of environmental factors on feeding in humans remain poorly understood. The overall aim of this proposal is to employ behavioral and functional neuroimaging methods to test a novel model for how the environment and metabolism influence processing in the amygdala-hypothalamic circuit to promote overeating. The proposed studies will further our understanding of the brain mechanisms mediating the influence of environmental factors on food intake and body weight in humans, and in particular proposes human amygdala neural responses to environmental factors as a quantitative predictor of weight gain susceptibility over extended periods of time.